Identification of transforming growth factor-beta as a contaminant in factor VIII concentrates: a possible link with immunosuppressive effects in hemophiliacs

Wadhwa, Meenu; Dilger, Paula; Tubbs, Jill; Mire-Sluis, AR; Barrowcliffe, Trevor W.; Thorpe, Robin

doi:10.1182/blood.v84.6.2021.bloodjournal8462021

Cited by 18 publications

(33 citation statements)

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“…A puri®ed chicken anti-TGF-b1 neutralizing antibody was kindly donated by Dr M. Wadhwa (National Institute for Biological Standards and Control, Potters Bar). According to data published by Wadhwa et al (1994), a 1:200 dilution of this antibody is capable of neutralizing 5 ng/ml of TGF-b1. A second polyclonal neutralizing antibody reactive with all isoforms of TGF-b (R & D Systems Ltd, U.K.) was also used to neutralize any TGF-b activity in coagulation factor concentrates.…”

Section: Methodsmentioning

confidence: 99%

“…using two different approaches. Triplicate wells containing a total volume of 100 ml of a 1:200 dilution of the puri®ed chicken anti-TGF-b1, used by Wadhwa et al (1994) in their experiments, and 1 IU/ml of a coagulation factor concentrate were incubated at 378C for 1 h before the addition of PBMC. For the second approach triplicate serial doubling dilutions of the commercial neutralizing antibody to TGF-b in culture medium, plus 1 or 2 IU/ml of coagulation factor concentrate were incubated at 378C for 1 h before the addition of PBMC.…”

Section: Methodsmentioning

confidence: 99%

“…(From this graph it was determined that 2 IU/ml HPVIII causes 84% inhibition.) (Wadhwa et al, 1994). Concentrates were present at a ®nal concentration of 1 IU/ml.…”

Section: Estimation Of Tgf-b Levels In Coagulation Factor Concentratesmentioning

confidence: 99%

“…Individuals with haemophilia receiving coagulation factor replacement therapy may have abnormalities of the immune system, irrespective of HIV status. These immune disturbances may be caused by the massive protein load, speci®c impurities, or the effects of viruses in the therapeutic concentrates (Schulman, 1991;Wadhwa et al, 1994;Evans et al, 1995;Pasi et al, 1995). Whether the observed changes in the immune system are of clinical importance remains controversial (Goedert et al, 1989;De Biasi et al, 1991;Hay et al, 1998).…”

mentioning

confidence: 99%

“…One speci®c constituent of many coagulation factor preparations that has been claimed to be a major contributor to immune modulating activity is the cytokine transforming growth factor-b (TGF-b) (Wadhwa et al, 1994). TGF-b comprises a family of multifunctional peptides that regulate cellular growth and differentiation.…”

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confidence: 99%

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TGF‐β is not the principal immunosuppressive component in coagulation factor concentrates

et al. 1999

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Summary. Coagulation factor concentrates are known to inhibit a variety of immune reactions when assessed in vitro. This study assessed the immunomodulatory activity of a wide range of coagulation factor concentrates by measuring their inhibition of PHA-stimulated lymphocyte proliferation and reduction in IL-2 secretion. The hypothesis that TGF-b is responsible for most of these effects was tested by measuring biologically active TGF-b and immunoreactive TGF-b1 in the concentrates and comparing the levels recorded with immunosuppressive activity. In addition, the coagulation factors were compared directly with a standard preparation of TGF-b in a TGF-b-speci®c bioassay and in lymphocyte proliferation assays. Although there was a broad correlation between levels of total or active TGF-b and immunosuppressive activity across all of the coagulation factors tested, individual data sets showed clear discrepancies. Implying that TGF-b probably serves as a surrogate marker for other immunomodulatory contaminants and that neither TGF-b nor any other single substance could account for all of the immunosuppressive activity observed. Furthermore, there was a difference of more than 100-fold in the relative potencies of coagulation factors and pure TGF-b, when compared in immunosuppression assays, indicating that the different assays did not measure the same substance. Whereas anti-TGF-b antibody almost completely blocked the activity of coagulation factor concentrates (TGF-bspeci®c bioassay) and abrogated the effect of authentic TGF-b (immunosuppression assays) at high concentrations it achieved <50% reversal of the immunosuppressive effects of coagulation factors in immunosuppression assays. These ®ndings indicated that TGF-b accounted for only a minor proportion of the immunosuppressive activity in most coagulation factor concentrates.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…(From this graph it was determined that 2 IU/ml HPVIII causes 84% inhibition.) (Wadhwa et al, 1994). Concentrates were present at a ®nal concentration of 1 IU/ml.…”

Section: Estimation Of Tgf-b Levels In Coagulation Factor Concentratesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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TGF‐β is not the principal immunosuppressive component in coagulation factor concentrates

et al. 1999

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Interferon‐γ secretion defects in haemophilia A patients receiving highly purified plasma‐derived or recombinant factor VIII

et al. 1996

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The outcome of developing immune responses is influenced by interactions among a large and complex network of secreted cytokines. T-cell secretion of interferon-gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha) and TNF-beta, or lymphotoxin contributes to the development of cell-mediated immunity, whereas secretion of interleukin (IL)-4, IL-5 and IL-6 contributes to development of humoral immunity. Humoral immunity to factor VIII (FVIII) develops in approximately 25% of severe haemophilia A patients. The aim of our research was to understand the underlying immune response to FVIII in patients with FVIII inhibitors. We report a defect in IFN-gamma secretion by peripheral blood mononuclear cells (PBMC) derived from haemophilia A patients, which was accompanied by a low level of mitogen-induced proliferation and a significant decrease in the percentage of natural killer (NK) cells. All of the observed defects were found in haemophilia A patients, both with and without FVIII inhibitors, who were free of viral infection and had been treated predominantly or exclusively with monoclonal antibody-purified or recombinant FVIII.

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The effect of monoclonal or ion‐exchange purified factor VIII concentrate on HIV disease progression: a prospective cohort comparison

et al. 1998

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The CD4 count has been reported to decline less rapidly in HIV-infected haemophiliacs treated with monoclonally purified factor VIII concentrates than in those using intermediate-purity concentrates. No survival advantage has been demonstrated for this effect, and it is unclear whether this effect occurs with all high-purity concentrates. Two cohorts of patients with severe haemophilia A and HIV treated with either ion-exchange-purified or monoclonally-purified concentrates were compared. The CD4 count, survival, AIDS-defining illnesses, CDC category and anti-retroviral therapy were recorded at 6-monthly intervals for 3 years following the change from intermediate to high-purity factor VIII. 116 patients were recruited, 37 of whom were treated with an ion-exchange purified factor VIII concentrate at three centres, mean (SD) age 31.1 (12.2) years, and 79 were treated with monoclonally purified factor VIII concentrate at two centres, mean (SD) age 29.8 (11.2) years. At the start of the study the median CD4 count was (monoclonal v ion-exchange) 0.30 v 0.16 x 10(9)/l. The CD4 count declined in both arms to a median of (monoclonal v ion-exchange) 0.16 v 0.08 x 10(9)/l at the final visit. Analysis of the (CD4 count)(1/2) over time, using a random coefficients model, found that the mean (SE) rates of decline were not statistically significantly different in the two treatment groups (monoclonal v ion exchange: -0.050 (0.008) v -0.034 (0.011) (CD4 count)(1/2) per year, P = 0.24). No statistically significant difference in survival (log-rank test: P = 0.33) was found. There was no difference in the proportion of individuals experiencing one or more AIDS-defining illnesses (P = 0.32) or in the proportion progressing to CDC category IV (P = 0.28) during the study. The CD4 count declined during the study at a rate similar to that previously reported in patients treated with intermediate-purity factor VIII concentrate, and there was no evidence of any difference between the two treatment groups.

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Identification of transforming growth factor-beta as a contaminant in factor VIII concentrates: a possible link with immunosuppressive effects in hemophiliacs

Cited by 18 publications

References 0 publications

TGF‐β is not the principal immunosuppressive component in coagulation factor concentrates

TGF‐β is not the principal immunosuppressive component in coagulation factor concentrates

Interferon‐γ secretion defects in haemophilia A patients receiving highly purified plasma‐derived or recombinant factor VIII

The effect of monoclonal or ion‐exchange purified factor VIII concentrate on HIV disease progression: a prospective cohort comparison

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